Interpretive Handbook

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89459 :
TGFBR1, Full Gene Sequence

Mutations in the TGFBR1 gene have been implicated in a range of autosomal dominant conditions with a considerable degree of phenotypic overlap. The genetic disease most commonly associated with TGFBR1 mutations is Loeys-Dietz syndrome (LDS), which is characterized by cerebral, thoracic and abdominal arterial aneurysms and/or dissections, as well as skeletal anomalies (chest abnormalities, scoliosis, joint laxity, arachnodactyly). LDS can also be caused by mutations in the TGFBR2 gene.

LDS is divided into LDS type I and LDS type II based on phenotype, then further categorized depending on the causative gene. Both LDS type I and II involve the cardiovascular and skeletal manifestations mentioned above. In addition, LDS type I involves craniofacial manifestations including hypertelorism, bifid uvula/cleft palate, and craniosynostosis. LDS type I caused by a TGFBR1 mutation is known as LDS1A, whereas LDS type I caused by a TGFBR2 mutation is known as LDS1B. LDS type II has cutaneous manifestations including velvety and translucent skin, easy bruising, widened and atrophic scars, and uterine rupture. LDS type II caused by a TGFBR1 mutation is known as LDS2A, whereas LDS type II caused by a TGFBR2 mutation is known as LDS2B. Identical mutations can lead to LDS type I or type II, supporting the belief that both types are part of a clinical continuum.

Mutations in the TGFBR1 genehave also been identified in conditions with phenotypic overlap with LDS. Marfan syndrome (MFS) is a systemic connective tissue disorder involving the ocular, skeletal, and cardiovascular systems. MFS is most often associated with mutations in the FBN1 gene; however some individuals who meet or nearly meet the clinical diagnostic criteria for MFS have been shown to have mutations in the TGFBR1 gene.

Some individuals with mutations in TGFBR1 present with features similar to those seen in vascular type Ehlers-Danlos syndrome (EDS type IV), such as visceral rupture, easy bruising, wide and atrophic scars, joint laxity, translucent skin, velvety skin, or both. In addition, familial thoracic aortic aneurysm and dissection (FTAAD), which involves cardiovascular manifestations only, has been associated with mutations in TGFBR1. Mutations in TGFBR1 may also be observed inShprintzen Goldberg syndrome (SGS), which is characterized by craniosynostosis, distinctive craniofacial features, skeletal changes, neurologic abnormalities, mental retardation, and brain anomalies among other features.

The TGFBR1 gene, which contains 9 exons and is located on chromosome 9q22, encodes the transforming growth factor beta receptor I (TGF beta R-I). TGF beta R-I is a 53 kilodalton protein that belongs to the serine-threonine kinase family of cell surface receptors. This group of receptors regulates a variety of cellular processes, including proliferation, differentiation, cell cycle arrest, apoptosis, and formation of the extracellular matrix. Receptor activation occurs upon binding of TGF beta to transforming growth factor beta receptor II (TGF beta R-II), which then recruits and phosphorylates TGF beta R-I, propagating the signal to downstream transcription factors.

Few genotype-phenotype correlations exist for TGFBR1 mutations; indeed, identical mutations have been reported to cause Marfan-like syndrome in some individuals, LDS in others, and FTAAD in others. Approximately 25% of individuals with LDS have an affected parent; while 75% have a de novomutation (de novorate for related phenotypes is not reported).

TGFBR1 mutations can manifest with a range of phenotypes and variable ages of onset both between families and amongst affected members of the same family. Thus, TGFBR1-related disorders can be diagnostically challenging. Genetic testing for TGFBR1 mutations allows for the confirmation of a suspected genetic disease. Confirmation of LDS or other TGFBR1-associated genetic diseases allows for proper treatment and management of the disease. Additionally, mutation confirmation can allow for preconception/prenatal and family counseling.

Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.

Absence of a mutation does not preclude the diagnosis of Loeys-Dietz syndrome or another TGFBR1-related disorder unless a specific mutation has already been identified in an affected family member. To test family members for a previously identified familial mutation, see TGFK1 / TGFBR1 Gene, Known Mutation.

This method will not detect mutations that occur in the introns (except in the splicing regions) and regulatory regions of the gene and large rearrangement-type mutations.

Rare, undocumented polymorphisms may be present which could lead to false-negative or positive results.

Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of appropriate family members may be useful to determine pathogenicity of the alteration.